Temperature-insensitive membrane materials and analyte sensors containing the same

ABSTRACT

Membranes permeable to an analyte may overlay the active sensing region of a sensor to limit the analyte flux and improve the response linearity of the sensor. Temperature variation of the analyte permeability can be problematic in some instances. Polymeric membrane compositions having limited variation in analyte permeability as a function of temperature may comprise: a polymer backbone comprising one or more side chains that comprise a heterocycle; and an amine-free polyether arm appended, via an alkyl spacer or a hydroxy-functionalized alkyl spacer, to the heterocycle of at least a portion of the one or more side chains.

BACKGROUND

The detection of various analytes within an individual can sometimes bevital for monitoring the condition of their health. Deviation fromnormal analyte levels can often be indicative of a number ofphysiological conditions. Glucose levels, for example, can beparticularly important to detect and monitor in diabetic individuals. Bymonitoring glucose levels with sufficient regularity, a diabeticindividual may be able to take corrective action (e.g., by injectinginsulin to lower glucose levels or by eating to raise glucose levels)before significant physiological harm occurs. Other analytes commonlysubject to physiological dysregulation that may similarly be desirableto monitor include, but are not limited to, lactate, oxygen, pH, A1c,ketones, drug levels, and the like.

Analyte monitoring in an individual may take place periodically orcontinuously over a period of time. Periodic analyte monitoring may takeplace by withdrawing a sample of bodily fluid, such as blood, at settime intervals and analyzing ex vivo. Continuous analyte monitoring maybe conducted using one or more sensors that remain at least partiallyimplanted within a tissue of an individual, such as dermally,subcutaneously or intravenously, so that analyses may be conducted invivo. Implanted sensors may collect analyte data continuously orsporadically, depending on an individual's particular health needsand/or previously measured analyte levels.

Periodic, ex vivo analyte monitoring can be sufficient to determine thephysiological condition of many individuals. However, ex vivo analytemonitoring may be inconvenient or painful for some persons. Moreover,there is no way to recover lost data if an analyte measurement is notobtained at an appropriate time.

Continuous analyte monitoring with an in vivo implanted sensor may be amore desirable approach for individuals having severe analytedysregulation and/or rapidly fluctuating analyte levels, although it canalso be beneficial for other individuals as well. While continuousanalyte monitoring with an implanted sensor can be advantageous, thereare challenges associated with these types of measurements. Intravenousanalyte sensors have the advantage of providing analyte concentrationsdirectly from blood, but they are invasive and can sometimes be painfulfor an individual to wear over an extended period. Subcutaneous anddermal analyte sensors can often be less painful for an individual towear and can provide sufficient measurement accuracy in many cases.

Although the entirety of a sensor may be implanted within an individual(e.g., surgically), it is often more desirable for primarily the activeportion of the sensor to be implanted internally (e.g., through a skinpenetration), with one or more additional sensor components remainingexternal to the individual's body. In certain instances, sensorssuitable for measuring analyte levels in vivo may extend from a sensorhousing that is designed to be worn “on-body” for extended periods oftime, such as upon the skin. Such on-body analyte sensors may beespecially desirable, since they often may be applied directly by awearer, rather than relying on a medical professional to perform aninvasive sensor implantation procedure.

Sensors may include a membrane disposed over at least the implantedportion of the sensor. In one aspect, the membrane may improvebiocompatibility of the sensor in vivo. In another aspect, the membranemay be permeable or semi-permeable to an analyte of interest but limitthe overall flux of the analyte to the active sensing portion of thesensor. Limiting access of the analyte to the active sensing portion ofthe sensor can aid in avoiding overloading (saturating) the activesensing components, thereby improving sensor performance and accuracy.For example, in the case of sensors employing enzyme-based detection,limiting access of the analyte to the sensor can make the chemicalkinetics of the sensing process analyte-limited rather thanenzyme-limited. With the enzymatic reaction being analyte-limited, readycalibration of the analyte sensor as a function of the sensor output maybe realized. That is, the sensor output may be correlated in some mannerto the amount of analyte when the enzymatic reaction is analyte-limited.In many instances, the sensor response may vary linearly as a functionof the analyte concentration in a biological fluid of interest when theenzymatic reaction is analyte-limited.

One issue associated with incorporating a membrane upon an analytesensor is that the analyte flux across the membrane may varyconsiderably as a function of temperature. While a calibration factor orequation may be employed to account for analyte flux variability as afunction of temperature, doing so can add considerable complexity to useof the sensor, especially if the analyte flux is non-linear with respectto temperature. Moreover, thermistors used in applying a calibrationequation may be complicated to operate and their size may thwart sensorminiaturization efforts. As another difficulty, the calibrationtemperature measurement location may not necessarily have the sametemperature as the membrane covering an active portion of the sensor.Other components of the sensor may likewise exhibit performancevariability with temperature (e.g., the enzymatic reaction rate in thecase of an enzyme-based sensor), which can make isolation andapplication of a calibration factor or equation for the membrane ratherdifficult. With increasing component complexity and performancevariability, higher costs and growing measurement errors may result.

BRIEF DESCRIPTION OF THE DRAWINGS

The following figures are included to illustrate certain aspects of thepresent disclosure, and should not be viewed as exclusive embodiments.The subject matter disclosed is capable of considerable modifications,alterations, combinations, and equivalents in form and function, withoutdeparting from the scope of this disclosure.

FIG. 1 shows a diagram of an illustrative analyte monitoring system thatmay incorporate an analyte sensor of the present disclosure.

FIG. 2 shows a diagram of an illustrative two-electrode sensorconfiguration compatible with the disclosure herein.

FIG. 3A shows a diagram of an illustrative three-electrode sensorconfiguration compatible with the disclosure herein. FIG. 3B shows adiagram of another configuration of an illustrative three-electrodesensor compatible with the disclosure herein.

FIG. 4 shows an illustrative plot of sensor response over a temperaturerange of 17° C.-42° C. at a fixed glucose concentration, wherein thesensing region is overcoated with a polymeric membrane compositiondescribed herein.

FIG. 5 shows an illustrative bar graph demonstrating the temperaturevariation over 5° C. increments for a sensor operating over atemperature range of 17° C.-42° C. at a fixed glucose concentration,wherein the sensing region is overcoated with a polymeric membranecomposition described herein.

FIG. 6 shows an illustrative plot of sensor response versus glucoseconcentration at a constant temperature, wherein the sensing region isovercoated with a polymeric membrane composition described herein.

DETAILED DESCRIPTION

The present disclosure generally describes analyte sensors suitable forin vivo use and, more specifically, membrane materials that exhibitlimited analyte permeability variation as a function of temperature andanalyte sensors incorporating such membrane materials.

As discussed above, in vivo analyte sensors may incorporate a membranematerial in order to improve biocompatibility and to limit access of ananalyte to the active sensing region of the sensor. Limiting analyteaccess to the sensing region can aid in avoiding sensor saturation,thereby improving sensor performance and accuracy. In the case of anenzymatic sensor, for example, a membrane material can promote ananalyte-limited detection process rather than an enzyme-limiteddetection process. With the detection process being analyte-limited,ready sensor calibration may be realized. In some instances, the sensorresponse may vary linearly as a function of analyte concentration in ananalyte-limited detection process.

One difficulty associated with many membrane materials is that theiranalyte permeability may vary to a clinically significant degree as afunction of temperature. Analyte permeability variation as a function oftemperature can lead to problematic sensor calibration, especially ifthe permeability variation is non-linear with respect to temperature.While certain membrane materials are known to exhibit limited analytepermeability variation as a function of temperature, theirbiocompatibility properties may leave room for improvement. Further,some membrane materials may be difficult to purify following synthesis.

The present disclosure provides polymeric membrane compositions that, incertain embodiments, may provide a desirable combination of limitedanalyte permeability variation as a function of temperature andfavorable biocompatibility properties. More specifically, the polymericmembrane compositions disclosed herein include a polymer backbone havingone or more side chains that comprise a heterocycle (also referred toherein as a heterocyclic polymer), and an amine-free polyether armappended to at least a portion of the one or more side chains,particularly to at least a portion of the heterocycles. The amine-freepolyether arm may incorporate one or more polyethylene glycol portions(blocks) and one or more polypropylene glycol portions (blocks), whichmay be appended to the heterocycle via an alkyl spacer or ahydroxy-functionalized alkyl spacer. Other spacers such as carbonyls,carboxylic esters, or carboxamides, for example, may also be suitable insome embodiments. In some embodiments, a single polyethylene glycolportion may be bonded to a single polypropylene glycol portion in adiblock arrangement (e.g., in a A-B block pattern or a B-A blockpattern, where A is a polyethylene glycol block and B is a polypropyleneglycol block) in the amine-free polyether arms. In other more particularembodiments, the one or more polyethylene glycol portions and the one ormore polypropylene glycol portions may be present in alternating blocks,without intervening functionality being present (e.g., in an A-B-Apattern, according to some embodiments, or in a B-A-B pattern, accordingto other embodiments, where A is a polyethylene glycol block and B is apolypropylene glycol block). The amine-free polyether arms may likewisecomprise more than three alternating blocks, according to furtherembodiments of the present disclosure. Both the block pattern and numberof ether units in each block may be varied in the polymeric membranecompositions disclosed herein. In some embodiments, a terminalpolyethylene glycol unit within the amine-free polyether arm may beappended to the heterocycle or other side chain in the heterocyclicpolymer via the alkyl spacer or the hydroxy-functionalized alkyl spacer,or alternative spacers such as carbonyls, carboxylic esters, orcarboxamides. In other embodiments, a terminal polypropylene glycol unitwithin the amine-free polyether arm may be appended to the heterocycleor other side chain in the heterocyclic polymer via the alkyl spacer orthe hydroxyl-functionalized alkyl spacer, or alternative spacers such ascarbonyls, carboxylic esters, or carboxamides.

The polymeric membrane compositions of the present disclosure may besynthesized by reacting a heterocyclic polymer with a polyether armprecursor bearing a reactive functionality, such as a terminal leavinggroup, particularly an alkyl halide or a terminal epoxide. Morespecifically, a primary alkyl halide, such as a primary alkyl bromide,may terminate an amine-free polyether arm precursor and lead to an alkylspacer appending the amine-free polyether arm to a heterocycle. Epoxidetermination of the amine-free polyether arm precursor, in contrast,results in the amine-free polyether arm becoming appended to aheterocycle via a hydroxy-functionalized alkyl group, specifically analkyl group bearing a secondary hydroxyl functionality. Selection of aparticular amine-free polyether arm precursor, including the choice ofreactive functionality, may be based upon factors such as syntheticease, in vivo properties of the resulting polymer, and the like. In moreparticular configurations, a primary alkyl halide or an epoxide may bebonded to a polyethylene glycol portion of the amine-free polyether armprecursor (i.e., through a terminal ether linkage and intervening spacergroup). In other particular configurations, a primary alkyl halide or anepoxide may be bonded to a polypropylene glycol portion of theamine-free polyether arm precursor (i.e., through a terminal etherlinkage and intervening spacer group).

Advantageously, the amine-free polyether arm precursors described hereinmay be synthesized independently before being reacted with aheterocyclic polymer. Independent synthesis of the amine-free polyetherarm precursors may provide greater compositional homogeneity of the sidechains in the resulting polymeric membrane compositions, as compared tothat obtainable by stepwise growth of the arms from a polymer backbone,in which differing arm lengths may be produced. Moreover, by reacting anamine-free polyether arm precursor in one step with a polymer backbone,improved yields, greater synthetic convergency, and higher throughputmay be realized, which may allow changes in membrane properties to bemore readily correlated with structural variation. A further advantageof the polymeric membrane compositions disclosed herein is that theymay, in many instances, be synthesized with a higher degree of purityand compositional homogeneity than are comparable polymer compositionsbearing an amine functionality within the polyether arms.

A further advantage of the present disclosure is that the ratio ofpolyethylene oxide to polypropylene oxide within the presently disclosedpolymeric membrane compositions may be varied much more readily than insimilar polymer compositions bearing an amine functionality within thepolyether arms. More specifically, the distribution and ratio ofpolyethylene oxide to polypropylene oxide may be fixed within anamine-free polyether arm precursor before bonding to the heterocyclicpolymer takes place. Advantageously and surprisingly, this feature mayallow tailoring of the ratio of polyethylene glycol to polypropyleneglycol to promote a desired biological response in vivo, as discussedfurther herein.

At least some of the polymeric membrane compositions disclosed hereinmay exhibit low or non-existent cytotoxicity in vivo, as well as otherfavorable biocompatibility properties. In particular embodiments, theratio of polyethylene oxide to polypropylene oxide may tailor thebiocompatibility properties obtained, such that the polymeric membranecompositions may be characterized as having a cytotoxicity score of 2 orbelow, as measured by the Minimal Essential Elution Media Test. In someor other particular embodiments, the polymeric membrane compositionsdescribed herein meet the biocompatibility requirements specified inInternational Standards Organization (ISO) 10993-1 when evaluatedaccording to the test protocols specified therein.

As such, the polymeric membrane compositions disclosed herein can beparticularly advantageous for use in various in vivo analyte sensors,particularly when the analyte sensors are intended for extended wear. Itis to be appreciated, however, that the polymeric membrane compositionsdisclosed herein may also be utilized in ex vivo analyte sensors withoutdeparting from the scope of the present disclosure. In particularembodiments, the polymeric membrane compositions described herein may betemperature-insensitive toward permeability of glucose. Other analytessuch as lactate, for example, may also permeate through the polymericmembrane compositions at temperature-insensitive rates, which may differfrom that of glucose.

Accordingly, in some embodiments, polymeric membrane compositions of thepresent disclosure may comprise a polymer backbone comprising one ormore side chains that comprise a heterocycle, and an amine-freepolyether arm appended, via an alkyl spacer or a hydroxy-functionalizedalkyl spacer, to the heterocycle of at least a portion of the one ormore side chains. Such amine-free polyether arms are distinguished fromcrosslinkers (i.e., a group covalently joining two or more polymerbackbones together) by virtue of the characteristic that the amine-freepolyether arms are bonded to a single polymer backbone.

Polymers suitable for use in the various embodiments of the presentdisclosure may comprise a polymer backbone that is branched orunbranched and that is a homopolymer or a heteropolymer. Homopolymersmay be formed by polymerization of a single type of monomer.Heteropolymers (also referred to as copolymers) include two or moredifferent types of monomers bonded in a single polymer chain. Copolymerscan have a random, alternating, or block distribution of the differingmonomer units, according to various embodiments.

Heterocycles suitable for incorporation within the polymeric membranecompositions of the present disclosure may comprise any cyclic moietycontaining one or more carbon atoms in conjunction with any combinationof N, P, O, S or Si atoms, in which the cyclic moiety may be aromatic oraliphatic. Suitable functional groups incorporating a heteroatom withinan aliphatic or heteroaromatic cyclic moiety may include, for example,—O—, —S—, —S—S—, —O—S—, —NR¹R², ═N—, ═N—N═, —N═N—, —N═N—NR¹R², —PR³—,—P(O)₂—, —P(O)R³—, —O—P(O)₂—, —S—O—, —S(O)—, —S(O)₂—, and the like,wherein R¹-R³ are independently hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl,substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl,substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,heteroalkyl, substituted heteroalkyl, heteroaryl, substitutedheteroaryl, heteroarylalkyl or substituted heteroarylalkyl. Wherefeasible, any of R¹-R³ may be linear or branched. Substituted variantsof R¹-R³ may include any of the aforementioned groups in which a carbonatom or a hydrogen atom has been replaced by a heteroatom such as F, Cl,Br, I, N, P, O, S or Si. In illustrative but non-limiting embodiments,suitable substitutions may include, for example, halide groups, alcoholgroups, ketone groups, ether groups, thioether groups, disulfide groups,and the like.

In more specific embodiments, the polymer backbone may comprise aheterocyclic or heteroaromatic nitrogen moiety within the one or moreside chains. In still more specific embodiments, the polymer backbonemay comprise a heteroaromatic nitrogen moiety within the one or moreside chains. Suitable heteroaromatic nitrogen moieties may include, forexample, acridine, carbazole, carboline, cinnoline, imidazole, indazole,indole, indoline, indolizine, isoindole, isoindoline, isoquinoline,isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine,phenanthridine, phenanthroline, phenazine, phthalazine, pteridine,purine, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole,pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline,tetrazole, thiadiazole, thiazole, triazole, derivatives thereof, and thelike.

One or more co-monomers may be present in combination with a monomerunit bearing a heteroaromatic nitrogen moiety, according to someembodiments. Suitable co-monomers for incorporation in the polymericmembrane compositions of the present disclosure include, for example,styrene compounds, optionally bearing substitution on the aromatic ring.Substituted styrene compounds that may be suitable include, for example,alkyl-substituted styrenes, halogen-substituted styrenes,hydroxyl-substituted styrenes, or any combination thereof.

In more specific embodiments, polymeric membrane compositions of thepresent disclosure may comprise a polyvinylpyridine or apolyvinylimidazole, including any copolymer thereof. In particularembodiments, the polymeric membrane compositions of the presentdisclosure may comprise a polyvinylpyridine, particularly a copolymer ofvinylpyridine (particularly 4-vinylpyridine) and styrene, or apolyvinylimidazole, particularly a copolymer of vinylimidazole(particularly 2-vinylimidazole) and styrene. Substituted styrenes may beutilized in some embodiments.

According to certain embodiments, a suitable copolymer of4-vinylpyridine and styrene may comprise the repeating unit of Formula1, in which variables a and b are both positive integers, and Q isoptional functionality.

In some embodiments, variables a and b may independently range fromabout 1 to about 1000, including ranges of about 2 to about 950, orabout 5 to about 900, or about 10 to about 850, or about 15 to about800, or about 20 to about 750, or about 25 to about 700, or about 30 toabout 650, or about 35 to about 600, or about 40 to about 550, or about50 to about 500, or 1 to about 10. In some embodiments, a may be greaterthan b. In other embodiments, a may be less than b. Depending on themembrane properties desired, a ratio of a to b may range from about 1:1to about 1:100, or from about 1:1 to about 1:95, or from 1:1 to about1:80, or from 1:1 to about 1:75, or from about 1:1 to about 1:50, orfrom about 1:1 to about 1:25, or from about 1:1 to about 1:10, or fromabout 1:1 to about 1:5, or from about 1:1 to about 1:3, or from about1:1 to about 1:2, or from about 1:1 to about 100:1, or from about 1:1 toabout 95:1, or from about 1:1 to about 80:1, or from about 1:1 to about75:1, or from about 1:1 to about 50:1, or from about 1:1 to about 25:1,or from about 1:1 to about 10:1, or from about 1:1 to about 5:1, or fromabout 1:1 to about 3:1, or from about 1:1 to about 2:1.

In some or other embodiments, a suitable copolymer of 4-vinylpyridineand styrene may have a styrene content ranging from about 0.01% to about50% mole percent, or from about 0.05% to about 45% mole percent, or fromabout 0.1% to about 40% mole percent, or from about 0.5% to about 35%mole percent, or from about 1% to about 30% mole percent, or from about2% to about 25% mole percent, or from about 5% to about 20% molepercent. Substituted styrenes may be used similarly and in similaramounts.

According to some or other various embodiments, a suitable copolymer of4-vinylpyridine and styrene may have a molecular weight of 5 kDa ormore, or about 10 kDa or more, or about 15 kDa or more, or about 20 kDaor more, or about 25 kDa or more, or about 30 kDa or more, or about 40kDa or more, or about 50 kDa or more, or about 75 kDa or more, or about90 kDa or more, or about 100 kDa or more. In more specific embodiments,a suitable copolymer of 4-vinylpyridine and styrene may have a molecularweight ranging from about 5 kDa to about 150 kDa, or from about 10 kDato about 125 kDa, or from about 15 kDa to about 100 kDa, or from about20 kDa to about 80 kDa, or from about 25 kDa to about 75 kDa, or fromabout 30 kDa to about 60 kDa. Other polymers suitable for use in thepolymeric membrane compositions of the present disclosure may havemolecular weight values falling within similar ranges.

In the polymeric membrane compositions of the present disclosure, anamine-free polyether arm may be appended to the heterocycle of at leasta portion of the side chains in the heterocyclic polymer. For example,in the case of a polyvinylpyridine, the amine-free polyether arm may becovalently bonded to the pyridine ring, particularly via the pyridinenitrogen atom. The fraction of side chains in the polymeric membranecompositions with an amine-free polyether arm appended thereto may beabout 0.1% or above of the available heterocycles in the heterocyclicpolymer, or about 0.2% or above of the available heterocycles in theheterocyclic polymer, or about 0.3% or above of the availableheterocycles in the heterocyclic polymer, or about 0.4% or above of theavailable heterocycles in the heterocyclic polymer, or about 0.5% orabove of the available heterocycles in the heterocyclic polymer, orabout 0.6% or above of the available heterocycles in the heterocyclicpolymer, or about 0.7% or above of the available heterocycles in theheterocyclic polymer, or about 0.8% or above of the availableheterocycles in the heterocyclic polymer, or about 0.9% or above of theavailable heterocycles in the heterocyclic polymer, or about 1.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 1.2% or above of the available heterocycles in the heterocyclicpolymer, or about 1.4% or above of the available heterocycles in theheterocyclic polymer, or about 1.6% or above of the availableheterocycles in the heterocyclic polymer, or about 1.8% or above of theavailable heterocycles in the heterocyclic polymer, or about 2.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 2.2% or above of the available heterocycles in the heterocyclicpolymer, or about 2.4% or above of the available heterocycles in theheterocyclic polymer, or about 2.6% or above of the availableheterocycles in the heterocyclic polymer, or about 2.8% or above of theavailable heterocycles in the heterocyclic polymer, or about 3.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 3.5% or above of the available heterocycles in the heterocyclicpolymer, or about 4.0% or above of the available heterocycles in theheterocyclic polymer, or about 4.5% or above of the availableheterocycles in the heterocyclic polymer, or about 5.0% or above of theavailable heterocycles in the heterocyclic polymer, or about 5.5% orabove of the available heterocycles in the heterocyclic polymer, orabout 6.0% or above of the available heterocycles in the heterocyclicpolymer, or about 6.5% or above of the available heterocycles in theheterocyclic polymer, or about 7.0% or above of the availableheterocycles in the heterocyclic polymer, or about 7.5% or above of theavailable heterocycles in the heterocyclic polymer, or about 8.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 8.5% or above of the available heterocycles in the heterocyclicpolymer, or about 9.0% or above of the available heterocycles in theheterocyclic polymer, or about 9.5% or above of the availableheterocycles in the heterocyclic polymer, or about 10% or above of theavailable heterocycles in the heterocyclic polymer. In more specificembodiments, an amine-free polyether arm may be appended to betweenabout 0.1% and about 5% of the available heterocycles in theheterocyclic polymer, or between about 0.5% and about 4.5% of theavailable heterocycles in the heterocyclic polymer, or between about1.0% and about 4.0% of the available heterocycles in the heterocyclicpolymer, or between about 1.5% and about 3.0% of the availableheterocycles in the heterocyclic polymer, or between about 1.5% andabout 2.5% of the available heterocycles in the heterocyclic polymer.

In alternative embodiments, the amine-free polyether arm may be appendedto a non-heterocycle side chain of the heterocyclic polymer, such as viacovalent bonding to an optionally substituted phenyl group.

In some embodiments, at least a portion of the available heterocycles inthe heterocyclic polymer may also have a crosslinker appended thereto.That is, in some embodiments, the polymeric membrane compositions of thepresent disclosure may further comprise a crosslinker appended to atleast a portion of the one or more side chains and adjoining a firstpolymer backbone to a second polymer backbone. The crosslinker may beappended to the heterocyclic polymer in addition to the amine-freepolyether arm. In some embodiments, the crosslinker may itself be apolyether, such as a polyethylene glycol or a copolymer of ethyleneglycol and propylene glycol. Such crosslinkers are not limited in termsof the number of polyethylene glycol units that may be present. In somemore specific embodiments, an amount of heterocycles functionalized witha crosslinker may be greater than an amount of heterocyclesfunctionalized with an amine-free polyether arm. In other embodiments,an amount of heterocycles functionalized with a crosslinker may be lessthan an amount of heterocycles functionalized with an amine-freepolyether arm. In illustrative embodiments, a bis-epoxide polyethyleneglycol compound may be used to form a polymeric membrane compositionbearing a crosslinker.

In more specific embodiments, the fraction of side chains that may havea crosslinker appended thereto may be about 0.1% or above of theavailable heterocycles in the heterocyclic polymer, or about 0.2% orabove of the available heterocycles in the heterocyclic polymer, orabout 0.3% or above of the available heterocycles in the heterocyclicpolymer, or about 0.4% or above of the available heterocycles in theheterocyclic polymer, or about 0.5% or above of the availableheterocycles in the heterocyclic polymer, or about 0.6% or above of theavailable heterocycles in the heterocyclic polymer, or about 0.7% orabove of the available heterocycles in the heterocyclic polymer, orabout 0.8% or above of the available heterocycles in the heterocyclicpolymer, or about 0.9% or above of the available heterocycles in theheterocyclic polymer, or about 1.0% or above of the availableheterocycles in the heterocyclic polymer, or about 1.2% or above of theavailable heterocycles in the heterocyclic polymer, or about 1.4% orabove of the available heterocycles in the heterocyclic polymer, orabout 1.6% or above of the available heterocycles in the heterocyclicpolymer, or about 1.8% or above of the available heterocycles in theheterocyclic polymer, or about 2.0% or above of the availableheterocycles in the heterocyclic polymer, or about 2.2% or above of theavailable heterocycles in the heterocyclic polymer, or about 2.4% orabove of the available heterocycles in the heterocyclic polymer, orabout 2.6% or above of the available heterocycles in the heterocyclicpolymer, or about 2.8% or above of the available heterocycles in theheterocyclic polymer, or about 3.0% or above of the availableheterocycles in the heterocyclic polymer, or about 3.5% or above of theavailable heterocycles in the heterocyclic polymer, or about 4.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 4.5% or above of the available heterocycles in the heterocyclicpolymer, or about 5.0% or above of the available heterocycles in theheterocyclic polymer, or about 5.5% or above of the availableheterocycles in the heterocyclic polymer, or about 6.0% or above of theavailable heterocycles in the heterocyclic polymer, or about 6.5% orabove of the available heterocycles in the heterocyclic polymer, orabout 7.0% or above of the available heterocycles in the heterocyclicpolymer, or about 7.5% or above of the available heterocycles in theheterocyclic polymer, or about 8.0% or above of the availableheterocycles in the heterocyclic polymer, or about 8.5% or above of theavailable heterocycles in the heterocyclic polymer, or about 9.0% orabove of the available heterocycles in the heterocyclic polymer, orabout 9.5% or above of the available heterocycles in the heterocyclicpolymer, or about 10% or above of the available heterocycles in theheterocyclic polymer. In more specific embodiments, a crosslinker may beappended to between about 1% and about 20% of the available heterocyclesin the heterocyclic polymer, or between about 2% and about 10% of theavailable heterocycles in the heterocyclic polymer, or between about 3%and about 8% of the available heterocycles in the heterocyclic polymer,or between about 4% and about 9% of the available heterocycles in theheterocyclic polymer, or between about 5% and about 12% of the availableheterocycles in the heterocyclic polymer.

Alternatively, in some embodiments, at least a portion of thenon-heterocycle side chains of the heterocyclic polymer, such as anoptionally substituted phenyl group, may have a crosslinker appendedthereto.

According to various embodiments, the amine-free polyether arm may bebound to the polymer backbone in the polymeric membrane compositionsdisclosed herein via a heteroatom within at least a portion of theheterocycles in the one or more side chains of the heterocyclic polymer.Alternative embodiments may include those in which the amine-freepolyether arm is bound to the polymer backbone via a carbon atom of atleast a portion of the heterocycles in the one or more side chainsand/or via a carbon atom in an optionally substituted phenyl group inthe polymer backbone. In more specific embodiments, the amine-freepolyether arm may be bound to the polymer backbone via a heterocyclic orheteroaromatic nitrogen atom within the one or more side chains. Forexample, in the case of the polymer backbone being polyvinylpyridine ora copolymer thereof, the amine-free polyether arm may be appended to aside chain via the pyridine nitrogen atom. When functionalized with anamine-free polyether arm or a crosslinker, the pyridine nitrogen atom isin quaternized form.

Accordingly, in more specific embodiments, polymeric membranecompositions of the present disclosure, in which the amine-freepolyether arm is bonded to a pyridine nitrogen atom, may have repeatunits defined by Formulas 2 and 3 below, wherein variables a, b and Qare defined as above, c is a positive

integer not greater than a, and Z is an amine-free polyether arm, acrosslinker, or any combination thereof. When both an amine-freepolyether arm and a crosslinker are present, the polymeric membranecompositions may have a structure defined by one or more of Formulas4-7, wherein variables a, b and Q are

defined as above, c1 and c2 are positive integers whose sum is notgreater than a, d is specified by Equation 1, Z₁ is an amine-freepolyether arm, and Z₂ is ad=a−c1−c2  (Equation 1)crosslinker. As such, the heteroaromatic (pyridine) rings in theheterocyclic polymer may be functionalized with Z₁ and Z₂ in anycombination or pattern in the various polymeric membrane compositionembodiments of the present disclosure. That is, the repeat units definedby Formulas 2-7 may be present in any combination with one another indefining a heterocyclic polymer suitable for incorporation in thepolymeric membrane compositions of the present disclosure.

In other specific embodiments, polymeric membrane compositions havingthe amine-free polyether arm bonded to a pyridine moiety, but not viathe pyridine nitrogen atom, may be defined by Formulas 8 and 9 below,wherein variables a, b, c and Q and Z are defined as above.

Optionally, any of the pyridine nitrogen atoms in Formulas 8 and 9 maybe quaternized with an alkyl group (e.g., through reaction with an alkylhalide) when the amine-free polyether arm is bonded to a carbon atom ofthe pyridine. Any unsubstituted carbon atoms in the pyridine groups maybe bonded to an amine-free polyether arm and/or a crosslinker accordingto the embodiments described herein. When both an amine-free polyetherarm and a crosslinker are present, the amine-free polyether arm and thecrosslinker may be present upon the same pyridine group or differentpyridine groups.

In various embodiments, the amine-free polyether arm may comprise atleast one polyethylene oxide block and at least one polypropylene oxideblock. The amine-free polyether arm may comprise a diblock arrangementof polyethylene oxide and polypropylene oxide, according to someembodiments. That is, in some embodiments, the amine-free polyether armmay comprise, in order an alkyl spacer or a hydroxy-functionalized alkylspacer, a polyethylene oxide block and a polypropylene oxide block, andin other embodiments, the amine-free polyether arm may comprise, inorder, an alkyl spacer or a hydroxy-functionalized alkyl spacer, apolypropylene oxide block and a polyethylene oxide block. In other morespecific embodiments, the amine-free polyether arm may comprise, inorder, an alkyl spacer or a hydroxy-functionalized alkyl spacer, a firstpolyethylene oxide block, a polypropylene oxide block, and a secondpolyethylene oxide block (i.e., an A-B-A repeat pattern). In still othermore specific embodiments, the amine-free polyether arm may comprise, inorder, an alkyl spacer or a hydroxy-functionalized alkyl spacer, a firstpolypropylene oxide block, a polyethylene oxide block, and a secondpolypropylene oxide block (i.e., a B-A-B repeat pattern). The alkylspacer or the hydroxy-functionalized alkyl spacer may be bound to aheterocyclic or heteroaromatic nitrogen atom in a side chain of thepolymer backbone, according to various embodiments. Alternative bondingto any of the carbon atoms of a heterocyclic side chain or any of thecarbon atoms of a side chain phenyl group are also possible in someinstances. The alkyl spacer or the hydroxy-functionalized alkyl spacermay also be bound to the first polyethylene oxide block in theamine-free polyether arm, according to various embodiments, such asthrough a terminal ether linkage. The second polyethylene oxide blockmay be terminated by a methoxy group, according to some embodiments.Alternately, the alkyl spacer of the hydroxy-functionalized alkyl spacermay also be bound to a first polypropylene oxide block in the amine-freepolyether arm, and a second polypropylene oxide block may be terminatedby a methoxy group, according to some embodiments.

Accordingly, in various embodiments of the present disclosure, theamine-free polyether arm may have a structure defined by Formulas 10 or11 below,

wherein PE represents a polyethylene oxide block, PP represents apolypropylene oxide block, and L is a spacer group. Suitable spacergroups may include, but are not limited to alkyl, hydroxy-functionalizedalkyl, carbonyl, carboxylic ester, carboxamide, and the like. Variablesq, r, s, and t are positive integers defining the number of monomerunits in each block and the number of times the blocks are repeated,with the proviso that in diblock arrangements of polyethylene oxide andpolypropylene oxide applicable to Formulas 10 and 11, variable t may be0. In Formula 10 with t≠0, the terminal polyethylene oxide monomer unitmay be substituted with alkoxy group, such as a methoxy group. Likewise,in Formula 11 with t≠0, the terminal polypropylene oxide monomer unitmay be substituted with alkoxy group, such as a methoxy group. Diblockarrangements associated with Formulas 10 and 11, in which t=0, maysimilarly have alkoxy group termination. According to some embodiments,variable q is an integer ranging between about 2 and about 50 or betweenabout 6 and about 20, variable r is an integer ranging between about 2and about 60 or between about 10 and about 40, and variable t is aninteger ranging between about 2 and about 50 or between about 10 andabout 30. According to some or other various embodiments, variable s isan integer ranging between 1 and about 20 or between 1 and about 10. Insome embodiments, variable s is equal to 1. Diblock arrangements ofpolyethylene oxide and polypropylene oxide may include variables q and rwithin the same ranges as above, but with variable s equal to 1 andvariable t equal to 0.

In more specific embodiments of the present disclosure, the amine-freepolyether arm may have a structure defined by Formula 12, whereinvariable w

is 0 or 1, variable x is an integer ranging between about 4 and about 24or between about 6 and about 20, variable y is an integer rangingbetween about 8 and about 60 or between about 10 and about 40, andvariable z is an integer ranging between about 6 and about 36 or betweenabout 10 and about 30. Alternately, variable z may be 0 in a diblockarrangement, with the other variables residing in the same ranges. Inmore specific embodiments, variable x may range between about 8 andabout 16 or between about 9 and about 12, variable y may range betweenabout 10 and about 32, or between about 16 and about 30, or betweenabout 12 and about 20, and variable z may range between about 10 andabout 20 or between about 14 and about 18. In still other more specificembodiments, x may be 10, y may be 20 and z may be 14; or x may be 12, ymay be 16 and z may be 16; or x may be 14, y may be 12 and z may be 18.In some embodiments, x may be less than z, such that the secondpolyethylene oxide block is longer (larger) than the first polyethyleneoxide block.

In some embodiments, the ratio of (x+z):y in Formula 12 may be at leastabout 1.4:1, or at least about 1.7:1, or at least about 2:1, or at leastabout 2.5:1, or at least about 3:1, or at least about 3.5:1. In morespecific embodiments, the ratio of (x+z):y in Formula 12 may rangebetween about 1.4:1 to about 5:1, or between about 1.7:1 to about 3.2:1,or between about 2.2:1 to 3.0:1, or between about 2.6:1 and about 2.9:1,or between about 3:1 and about 5:1.

In some embodiments of the present disclosure, the amine-free polyetherarm may have a structure defined by Formula 13, wherein variable w

is 0 or 1, variable x is an integer ranging between about 4 and about 24or between about 6 and about 20, variable y is an integer rangingbetween about 8 and about 60 or between about 10 and about 40, andvariable z is an integer ranging between about 6 and about 36 or betweenabout 10 and about 30. Alternately, variable z may be 0 in a diblockarrangement, with the other variables residing in the same ranges. Inmore specific embodiments, variable x may range between about 6 andabout 16 or between about 9 and about 12, variable y may range betweenabout 10 and about 40, or between about 16 and about 30, or betweenabout 14 and about 32, and variable z may range between about 8 andabout 20 or between about 12 and about 16.

The amine-free polyether arms described herein may become bonded to aheterocycle in the side chain of a heterocyclic polymer by way of areactive functionality in an amine-free polyether arm precursor.Suitable reactive functionalities may include a halogen or an epoxide,for example, either of which may be reacted via nucleophilic attack fromthe side chain of the heterocyclic polymer. Halogen-functionalizedamine-free polyether arm precursors lead to amine-free polyether arms inwhich n is 0 (i.e., the spacer is an alkyl group), whereasepoxide-functionalized amine-free polyether arm precursors lead toamine-free polyether arms in which n is 1 (i.e., the spacer is a propylgroup bearing a secondary alcohol). In more specific embodiments, alkylspacers resulting from halogen-functionalized amine-free polyether armprecursors may include alkyl groups that are straight- or branched-chainand contain 2 to about 20 carbon atoms. In more specific embodiments,halides that may be suitably included in halogen-functionalizedamine-free polyether arm precursors include chloride or bromide, withbromide being chosen in more particular embodiments.

Formulas 14 and 15 show structures of illustrative amine-free polyetherarm precursors that may be suitably reacted with a heterocyclic polymerto form certain polymeric membrane compositions disclosed herein, inwhich variable x, y, and z are defined as above.

In Formula 14, variable A₁ represents an alkyl group having between 2and about 20 carbon atoms, such as between 2 and about 4 carbon atoms,or between 2 and about 6 carbon atoms, or between 2 and about 8 carbonatoms, and X is a halide, such as chloride or bromide. The alkyl groupof A₁ may be branched- or straight-chain and optionally containheteroatom substitution. Halide X may be a primary alkyl halide,according to various embodiments. In Formula 15, variable A₂ representsan alkyl group having between 1 and about 10 carbon atoms, such as 1carbon atom, 2 carbon atoms, 3 carbon atoms, or 4 carbon atoms. In someembodiments, the alkyl group of A₂ may be straight-chain, and in otherembodiments, the alkyl group A₂ may contain branching.

In more specific embodiments, suitable amine-free polyether armprecursors for forming the polymeric membrane compositions disclosedherein may include those shown in Formulas 16 and 17, in which thevariables are defined as above.

In some embodiments, a sulfonate-containing arm may be appended to atleast a portion of the one or more side chains in the heterocyclicpolymers disclosed herein. The sulfonate-containing arm may be presentin combination with any of the amine-free polyether arms disclosedherein and in any suitable ratio. In some embodiments, the polymericmembrane compositions disclosed herein may comprise a higher quantity ofamine-free polyether arms than sulfonate-containing arms.

According to more specific embodiments, a sulfonate-containing arm maybe appended to the heterocycle of a heterocyclic polymer via an alkylgroup. The alkyl group may contain between 1 and about 6 carbon atoms,or between 2 and about 4 carbon atoms, according to various embodiments.Suitable reagents for introducing a sulfonate-containing arm to theheterocyclic polymers disclosed herein may include halosulfonic acidcompounds such as chloromethanesulfonic acid, bromoethanesulfonic acid,or the like, or cyclic sulfonates (sultones).

In some embodiments, an amine-free polyether arm comprising a singletype of repeating ether unit may be appended to at least a portion ofthe one or more side chains in the heterocyclic polymers disclosedherein. Such amine-free polyether arms may be present in combinationwith a sulfonate-containing arm and/or an amine-free polyether armbearing two or more different types of ether unit blocks, such as thosedescribed by Formulas 10-13.

According to more specific embodiments, an amine-free polyether armcomprising a single type of repeating ether unit may be a polyethyleneoxide arm or a polypropylene oxide arm. In more particular embodiments,the amine-free polyether arm may be an amine-free polyethylene oxide armappended, via an alkyl spacer or a hydroxy-functionalized alkyl spacer,to the heterocycle of at least a portion of the one or more side chains.Between about 8 to about 25, or between about 10 to about 22, or betweenabout 12 to about 20 repeating ether units may be present in theamine-free polyether arm comprising a single type of repeating etherunit. The repeating polyethylene oxide or polypropylene oxide etherunits may be appended to the one or more side chains of the heterocyclicpolymer via an alkyl group or a hydroxyl-functionalized alkyl group. Thealkyl group may contain between 1 and about 6 carbon atoms, or between 2and about 4 carbon atoms, according to various embodiments. Thehydroxy-functionalized alkyl group may contain 3 carbon atoms with ahydroxyl group on the central carbon atom. An alkoxy group, particularlya methoxy group, may terminate the amine-free polyether arm opposite thepoint of attachment to the heterocyclic polymer. Such amine-freepolyether arms may be introduced to the heterocyclic polymer by reactinga polyether terminated with either an alkyl halide or an epoxide withthe heterocyclic polymer.

In some embodiments, the polymeric membrane compositions of the presentdisclosure may be crosslinked, as referenced in brief above. Crosslinkedpolymers suitable for incorporation in the polymeric membranecompositions may comprise a crosslinker that connects two or morepolymer backbones together with one another (intermolecularcrosslinking) or different portions of the same polymer backbonetogether with one another (intramolecular crosslinking). A “crosslinkingagent” containing two or more reactive functionalities may promote suchcrosslinking. Once crosslinking has occurred, a portion of thecrosslinking agent may remain as a crosslinker, either intermolecularlyor intramolecularly linking polymer chain(s) to one another.

In some embodiments, suitable crosslinking agents may comprise apolyetherimine and a glycidyl ether, such as diglycidyl ether. Thiscombination of reagents forms crosslinks containing an amine group. Inother embodiments, suitable crosslinking agents may comprise a polyetherand a glycidyl ether, such as diglycidyl ether, which leads tocrosslinks lacking an amine group. In more particular embodiments,suitable crosslinking agents for forming amine-free crosslinks maycomprise a polyethylene oxide/polypropylene oxide copolymer and aglycidyl ether, such as diglycidyl ether, or polyethylene oxide and aglycidyl ether, such as diglycidyl ether.

In some or other embodiments, suitable crosslinking agents may comprisea polyethylene oxide block having a terminal propylene oxide unit ateach end of the polyethylene oxide block. Such a crosslinking agent mayhave the structure shown in Formula 18, wherein variable n is a positiveinteger ranging

between about 10 and about 500, or between about 10 and about 100, orbetween about 10 and about 50, or between about 12 and about 36, orbetween about 12 and about 30, or between about 12 and about 28, orbetween about 12 and about 26, or between about 12 and about 24, orbetween about 12 and about 22, or between about 12 and about 20, orbetween about 14 and about 28, or between about 14 and about 24, orbetween about 16 and about 30, or between about 16 and about 24. As canbe appreciated by one having ordinary skill in the art, the crosslinkingagent of Formula 18 reacts to form a crosslink in which the polyethyleneoxide block is bound to a polymer backbone on each end via ahydroxy-functionalized alkyl group. Specifically, the crosslinking agentof Formula 18 produces the crosslinker of Formula 19 upon nucleophilicopening of the epoxide ring in each terminal propylene oxide unit,wherein n is defined as above.

Accordingly, in more specific embodiments of the present disclosure,suitable crosslinks may comprise at least one polyethylene oxide blockthat is bound on opposing ends to a first heterocycle of first polymerbackbone and a second heterocycle of a second polymer backbone, each viaa hydroxy-functionalized alkyl group. In such embodiments, the manner ofcrosslinking is intermolecular. In some or other embodiments of thepresent disclosure, such crosslinking agents may be bound on opposingends to first and second heterocycles within the same polymer backbone,each via a hydroxyl-functionalized alkyl group, in which case the mannerof crosslinking is intramolecular.

Crosslinking agents having additional epoxide groups may also be used insome embodiments, such as the illustrative tris-epoxide compound shownin Formula 20. Such crosslinking agents may lead to the formation ofcrosslinks between more than two polymer backbones.

Optionally, such crosslinking agents may be further reacted with apolyethylene glycol, a polypropylene glycol, or an ethyleneglycol/propylene glycol copolymer to form a given crosslink.

Advantageously, the polymeric membrane compositions of the presentdisclosure may form temperature-insensitive membranes, according tovarious embodiments. As used herein, the term “temperature-insensitive”refers to the condition of a parameter of interest varying in aclinically or statistically insignificant manner as a function oftemperature over a given range. In more specific embodiments,temperature-insensitive membranes of the present disclosure may betemperature-insensitive with respect to the analyte permeability,particularly glucose. Other analytes may also exhibittemperature-insensitive membrane permeability, with the rate ofpermeation being the same as or different than that of glucose. As such,the limited variation in analyte permeability may lead to little or nochange in sensor response when assaying a fixed concentration of analyteover a given temperature range at which the polymeric membranecomposition is temperature-insensitive.

In more specific embodiments, the polymeric membrane compositions of thepresent disclosure may be temperature-insensitive toward analytepermeability (e.g., glucose) over a temperature range of about 10° C. toabout 70° C., or about 15° C. to about 65° C., or about 20° C. to about60° C., or about 25° C. to about 50° C., or about 15° C. to about 45°C., or about 15° C. to about 40° C. or about 20° C. to about 45° C., orabout 25° C. to about 40° C. In some or other more specific embodiments,the variation of the polymeric membrane compositions toward analytepermeability (e.g., glucose) may be about 10% or less over thetemperature range, or about 5% or less over the temperature range, orabout 2% or less over the temperature range, or about 1% or less overthe temperature range, or about 0.5% or less over the temperature range,or about 0.1% or less over the temperature range, or about 0.05% or lessover the temperature range, or about 0.01% or less over the temperaturerange. Within a subrange of the broader temperature range (e.g., about15° C. to about 45° C.), the variation of the polymeric membranecompositions toward analyte permeability may be about 2% or less orabout 1% or less over a given 5° C. temperature increment. Determinationof the variation of the polymeric membrane compositions toward analytepermeability may be ascertained by measuring the difference in sensorresponse over a specified temperature range at a fixed concentration ofanalyte (see FIG. 4 herein).

The polymeric membrane compositions described herein may be furthercharacterized in terms of their biocompatibility properties. In variousembodiments, the polymeric membrane compositions may be characterized ashaving a cytotoxicity score of 2, or a cytotoxicity score of 1, or acytotoxicity score of 0. Such cytotoxicity scores may be present incombination with characteristics such as lack of hemolysis,mutagenicity, irritation, and similar properties. In some embodiments,the polymeric membrane compositions of the present disclosure meet orexceed ISO 10993-1 standards. ISO 10993-1 standards for tissue-implanteddevices include clinical lack of the following: cytotoxicity,sensitization, irritation or intracutaneous reactivity, acute systemictoxicity, pyrogenicity, subacute or subchronic toxicity, genotoxicity,and implantation issues.

The polymeric membrane compositions disclosed hereinabove may be presentin an analyte sensor, according to various embodiments. Accordingly,analyte sensors of the present disclosure may comprise a sensing region(i.e., an active portion of the sensor), and a polymeric membranecomposition overlaying the sensing region. The polymeric membranecomposition may comprise a polymer backbone comprising one or more sidechains that comprise a heterocycle, and an amine-free polyether armappended, via an alkyl spacer or a hydroxyl-functionalized alkyl spacer,to the heterocycle of at least a portion of the one or more side chains.Any of the polymeric membrane compositions may be utilized inconjunction with an analyte sensor, as discussed further herein.

In some embodiments, the sensing region of the analyte sensors of thepresent disclosure may comprise an enzyme. The enzyme may catalyze areaction that consumes an analyte of interest or produces a product thatis detectable by the analyte sensor. The enzyme may be covalently bondedto a polymer comprising at least a portion of the sensing region,according to some embodiments. Choice of a particular enzyme may bedictated by the analyte of interest to be detected. Glucose oxidase orglucose dehydrogenase (e.g., pyrroloquinoline quinone (PQQ), dependentglucose dehydrogenase, flavine adenine dinucleotide (FAD) dependentglucose dehydrogenase, or nicotinamide adenine dinucleotide (NAD)dependent glucose dehydrogenase) may be used when the analyte ofinterest is glucose. Lactate oxidase or lactate dehydrogenase may beused when the analyte of interest is lactate. Laccase may be used whenthe analyte of interest is oxygen or when oxygen is generated orconsumed in response to a reaction of the analyte. Other enzymes may beemployed similarly for detecting other analytes of interest, as will beappreciated by one having ordinary skill in the art and the benefit ofthe present disclosure. Any of the substrates acted upon by theforegoing enzymes or other enzymes may be an analyte suitable foranalysis with the analyte sensors disclosed herein.

Additional details of illustrative analyte sensors that may be used inconjunction with the polymeric membrane compositions of the presentdisclosure are discussed in further detail hereinafter. It is to beappreciated, however, that analyte sensors having differentarchitectures and components other than those expressly disclosed hereinmay be suitably used as well.

FIG. 1 shows a diagram of an illustrative analyte monitoring system thatmay incorporate an analyte sensor of the present disclosure. As shown,analyte monitoring system 100 includes sensor control device 102 andreader device 120 that are configured to communicate with one anotherover a local communication path or link, which may be wired or wireless,uni- or bi-directional, and encrypted or non-encrypted. Reader device120 may also be in communication with remote terminal 170 and/or trustedcomputer system 180 via communication path(s)/link(s) 141 and/or 142,respectively, which also may be wired or wireless, uni- orbi-directional, and encrypted or non-encrypted. Any suitable electroniccommunication protocol may be used for each of the local communicationpaths or links. Reader device 120 may comprise display 122 and optionalinput component 121.

Sensor control device 102 includes sensor housing 103, which may includecircuitry and a power source for operating sensor 104. Sensor 104protrudes from sensor housing 103 and extends through adhesive layer105. Suitable adhesives for inclusion in adhesive layer 105 will befamiliar to one having ordinary skill in the art.

Sensor 104 is adapted to be at least partially inserted into a tissue ofinterest, such as the dermal layer of the skin. Sensor 104 may comprisea sensor tail of sufficient length for insertion to a desired depth in agiven tissue. The sensor tail may comprise a sensing region that isactive for sensing, and may comprise an enzyme, according to one or moreembodiments. The sensing region includes a polymeric membranecomposition of the present disclosure, according to various embodiments.One or more analyte levels may be determined using sensor 104 andundergo communication to reader device 120, according to one or moreembodiments. The analyte may be monitored in any biological fluid suchas dermal fluid, plasma, blood, lymph, or the like. Analytes that may bemonitored are not considered to be particularly limited. In certainembodiments, the analyte may be glucose. Other analytes of interest withrespect to human physiology may include, for example, lactate, oxygen,pH, A1c, ketones, drug levels, and the like. Any of these analytes mayexhibit temperature-insensitive permeability through the polymericmembrane compositions disclosed herein. Both single analytes and anycombination of the foregoing analytes may be assayed.

An introducer may be present transiently to promote introduction ofsensor 104 into a tissue. In illustrative embodiments, the introducermay comprise needle a 109. It is to be recognized that other types ofintroducers, such as sheaths or blades, may be present in alternativeembodiments. More specifically, the needle or similar introducer maytransiently reside in proximity to sensor 104 prior to insertion andthen be withdrawn afterward. While present, the needle or otherintroducer may facilitate insertion of sensor 104 into a tissue byopening an access pathway for sensor 104 to follow. For example, theneedle may facilitate penetration of the epidermis as an access pathwayto the dermis to allow implantation of sensor 104 to take place,according to one or more embodiments. After opening the access pathway,the needle or other introducer may be withdrawn so that it does notrepresent a sharps hazard. In illustrative embodiments, the needle maybe solid or hollow, beveled or non-beveled, and/or circular ornon-circular in cross-section. In more particular embodiments, theneedle may be comparable in cross-sectional diameter and/or tip designto an acupuncture needle, which may have a cross-sectional diameter ofabout 250 microns. It is to be recognized, however, that suitableneedles may have a larger or smaller cross-sectional diameter if neededfor particular applications. In alternative embodiments, needle 109 orsimilar introducers may be absent, provided sensor 104 is sufficientlyrobust to penetrate a tissue and establish communication with a bodilyfluid of interest.

In some embodiments, a tip of the needle may be angled over the terminusof sensor 104, such that the needle penetrates a tissue first and opensan access pathway for sensor 104. In other illustrative embodiments,sensor 104 may reside within a lumen or groove of the needle 109, withthe needle similarly opening an access pathway for sensor 104. In eithercase, the needle is subsequently withdrawn after facilitating insertion.

It is to be recognized that analyte monitoring system 100 may compriseadditional features and functionality that are not necessarily describedherein in the interest of brevity. Accordingly, the foregoingdescription of analyte monitoring system 100 should be consideredillustrative and non-limiting in nature.

Analyte sensors of the present disclosure may comprise two-electrode orthree-electrode detection motifs, according to various embodiments.Three-electrode motifs may comprise a working electrode, a counterelectrode, and a reference electrode. Two-electrode motifs may comprisea working electrode and a second electrode, in which the secondelectrode functions as both a counter electrode and a referenceelectrode (i.e., a counter/reference electrode). In both two-electrodeand three-electrode detection motifs, the sensing region of the analytesensors described herein may be in contact with the working electrode.In various embodiments, the various electrodes may be at least partiallystacked upon one another, as described in further detail hereinafter. Inalternative embodiments, the various electrodes may be spaced apart fromone another upon the insertion tail of an analyte sensor.

FIG. 2 shows a diagram of an illustrative two-electrode sensorconfiguration compatible with the disclosure herein. As shown, analytesensor 200 comprises substrate 212 disposed between working electrode214 and counter/reference electrode 216. Alternately, working electrode214 and counter/reference electrode 216 may be located upon the sameside of substrate 212 with a dielectric material interposed in between.Sensing region 218 is disposed as at least one spot on at least aportion of working electrode 214. Membrane 220 overcoats at leastsensing region 218 and may optionally overcoat some or all of workingelectrode 214 and/or counter/reference electrode 216 in someembodiments. One or both faces of sensor 200 may be overcoated withmembrane 220. Membrane 220 may comprise any of the polymeric membranecompositions disclosed herein.

Three-electrode sensor configurations may be similar to analyte sensor200, except for the inclusion of an additional electrode (FIGS. 3A and3B). With an additional electrode 217, counter/reference electrode 216then functions as either a counter electrode or a reference electrode,and the additional electrode 217 (FIGS. 3A and 3B) fulfills the otherfunction not otherwise fulfilled. The additional electrode 217 may bedisposed upon either working electrode 214 or counter/referenceelectrode 216, with a separating layer of dielectric material inbetween. For example, as depicted in FIG. 3A dielectric layers 219 a,219 b and 219 c separate electrodes 214, 216 and 217 from one another.Alternately, at least one of electrodes 214, 216 and 217 may be locatedupon the opposite face of substrate 212 (FIG. 3B). Thus, in someembodiments, electrode 214 (working electrode) and electrode 216(counter electrode) may be located upon opposite faces of substrate 212,with electrode 217 (reference electrode) being located upon one ofelectrodes 214 or 216 and spaced apart therefrom with a dielectricmaterial. Conducting layer 222, such as a silver/silver chloridereference, may be located upon electrode 217 (reference electrode),according to some embodiments. As with sensor 200 shown in FIG. 2 ,sensing region 218 may comprise a single spot or multiple spotsconfigured for detecting an analyte of interest.

Additional electrode 217 may optionally be overcoated with membrane 220in some embodiments. Although FIGS. 3A and 3B have depicted all ofelectrodes 214, 216 and 217 as being overcoated with membrane 220, it isto be recognized that it is only necessary for sensing region 218 to beovercoated in order to realize the benefits described herein. As such,the configurations shown in FIGS. 3A and 3B should be understood asbeing non-limiting of the embodiments disclosed herein. As intwo-electrode configurations, one or both faces of sensor 200 may beovercoated with membrane 220.

When coated upon sensing region 218, membrane 220 may have a thicknessranging between about 0.1 microns and about 1000 microns, or betweenabout 1 microns and about 500 microns, or between about 10 microns andabout 100 microns.

In some embodiments, sensing region 218 may comprise a polymer that isbonded to glucose oxidase or another enzyme and a low-potential osmiumcomplex electron transfer mediator, as disclosed in, for example, U.S.Pat. No. 6,134,461, which is incorporated herein by reference in itsentirety. Other suitable electron transfer mediators may comprise metalcompounds or complexes of ruthenium, iron, or cobalt, for example.Suitable ligands for the metal complexes may include, for example,bidentate or higher denticity ligands such as, for example, abipyridine, biimidazole, or pyridyl(imidazole). Other suitable bidentateligands may include, for example, amino acids, oxalic acid,acetylacetone, diaminoalkanes, or o-diaminoarenes. Any combination ofmonodentate, bidentate, tridentate, tetradentate, or higher denticityligands may be present in the metal complex to achieve a fullcoordination sphere.

The enzyme in sensing region 218 may be covalently bonded to a polymeror other suitable matrix via a crosslinking agent. Suitable crosslinkingagents for reaction with free amino groups in the enzyme (e.g., with thefree amine in lysine) may include crosslinking agents such as, forexample, polyethylene glycol diglycidylether (PEGDGE) or otherpolyepoxides, cyanuric chloride, N-hydroxysuccinimide, imidoesters, orderivatized variants thereof. Suitable crosslinking agents for reactionwith free carboxylic acid groups in the enzyme may include, for example,carbodiimides.

A variety of approaches may be employed to determine the concentrationof an analyte using analyte sensor 200. For example, the concentrationof the analyte may be monitored using any of coulometric, amperometric,voltammetric, or potentiometric electrochemical detection techniques.

Embodiments disclosed herein include:

A. Polymeric Membrane Compositions. The polymeric membrane compositionscomprise: a polymer backbone comprising one or more side chains thatcomprise a heterocycle; and an amine-free polyether arm appended, via analkyl spacer or a hydroxy-functionalized alkyl spacer, to theheterocycle of at least a portion of the one or more side chains.

B. Analyte sensors. The analyte sensors comprise: a sensing region; anda polymeric membrane composition overlaying the sensing region; whereinthe polymeric membrane composition comprises a polymer backbonecomprising one or more side chains that comprise a heterocycle, and anamine-free polyether arm appended, via an alkyl spacer or ahydroxy-functionalized alkyl spacer, to the heterocycle of at least aportion of the one or more side chains.

C. Polymeric membrane compositions having temperature insensitivity toglucose or other potential analytes. The polymeric membrane compositionsare temperature-insensitive to at least glucose permeability over atemperature range of about 15° C. to about 45° C. and meet or exceed ISO10993-1 standards.

Each of embodiments A and B may have one or more of the followingadditional elements in any combination

Element 1: wherein the polymer backbone comprises a polyvinylpyridine ora polyvinylimidazole.

Element 2: wherein the polymer backbone comprises a copolymer ofvinylpyridine and styrene.

Element 3: wherein the amine-free polyether arm comprises at least onepolyethylene oxide block and at least one polypropylene oxide block, theamine-free polyether arm being bound to a heterocyclic or heteroaromaticnitrogen atom in a side chain of the polymer backbone.

Element 4: wherein the amine-free polyether arm has a structure of

wherein w is 0 or 1, x ranges between about 4 and about 24, y rangesbetween about 8 and about 60, and z ranges between about 6 and about 36.

Element 5: wherein x ranges between about 8 and about 16, y rangesbetween about 10 and about 32, and z ranges between about 10 and about20.

Element 6: wherein x≤z.

Element 7: wherein a ratio of (x+z):y is at least about 1.7:1.

Element 8: wherein a ratio of (x+z):y ranges between about 1.7:1 andabout 5:1.

Element 9: wherein the polymeric membrane composition further comprisesa sulfonate-containing arm appended to at least a portion of the one ormore side chains.

Element 10: wherein the polymeric membrane composition further comprisesa crosslinker appended to at least a portion of the one or more sidechains and adjoining a first polymer backbone to a second polymerbackbone.

Element 11: wherein the sensing region comprises an enzyme.

Element 12: wherein the polymeric membrane composition furthercomprises: an amine-free polyethylene oxide arm appended, via an alkylspacer or a hydroxy-functionalized alkyl spacer, to the heterocycle ofat least a portion of the one or more side chains.

By way of non-limiting example, exemplary combinations applicable to Aand B include:

The composition of A in combination with elements 1 and 2; 1 and 3; 1and 4; 1, 4 and 5; 1, 4 and 6; 1, 4, 5 and 6; 1, 4 and 7; 1, 4, 5 and 7;1, 4 and 8; 1, 4, 5 and 8; 1 and 9; 1 and 10; 1 and 12; 1, 9 and 10; 2and 3; 2 and 4; 2, 4 and 5; 2, 4 and 6; 2, 4, 5, and 6; 2, 4 and 7; 2,4, 5 and 7; 2, 4 and 8; 2, 4, 5 and 8; 2 and 9; 2 and 10; 2, 9 and 10; 3and 4; 3, 4 and 5; 3, 4 and 6; 3, 4, 5 and 6; 3, 4 and 7; 3, 4, 5 and 7;3, 4 and 8; 3, 4, 5 and 9; 3 and 9; 3 and 10; 3, 9 and 10; 4 and 5; 4and 6; 4, 5 and 6; 4 and 7; 4, 5 and 7; 4 and 8; 4, 5 and 8; 4 and 9; 4and 10; 4, 9 and 10; 4 and 12; 9 and 10; 10 and 12; and 11 and 12. Theanalyte sensor of B in combination with elements 1 and 2; 1 and 3; 1 and4; 1, 4 and 5; 1, 4 and 6; 1, 4, 5 and 6; 1, 4 and 7; 1, 4, 5 and 7; 1,4 and 8; 1, 4, 5 and 8; 1 and 9; 1 and 10; 1, 9 and 10; 1 and 12; 2 and3; 2 and 4; 2, 4 and 5; 2, 4 and 6; 2, 4, 5, and 6; 2, 4 and 7; 2, 4, 5and 7; 2, 4 and 8; 2, 4, 5 and 8; 2 and 9; 2 and 10; 2, 9 and 10; 3 and4; 3, 4 and 5; 3, 4 and 6; 3, 4, 5 and 6; 3, 4 and 7; 3, 4, 5 and 7; 3,4 and 8; 3, 4, 5 and 9; 3 and 9; 3 and 10; 3, 9 and 10; 4 and 5; 4 and6; 4, 5 and 6; 4 and 7; 4, 5 and 7; 4 and 8; 4, 5 and 8; 4 and 9; 4 and10; 4, 9 and 10; 9 and 10; 4 and 12; 10 and 12; and 11 and 12, any ofwhich may be in further combination with element 11. The composition ofC may be used in combination with any of the elements applicable to A.

To facilitate a better understanding of the embodiments describedherein, the following examples of various representative embodiments aregiven. In no way should the following examples be read to limit, or todefine, the scope of the invention.

EXAMPLES

Example 1: Temperature Variability. A polyvinylpyridine copolymer withstyrene having an amine-free polyether arm with a structurecorresponding to Formula 12 (w=1, x=14, y=12, z=18) was coated on to aglucose responsive sensor. The coated sensor was then exposed to aglucose solution of fixed concentration, and the sensor response wasmeasured over a range of temperatures. FIG. 4 shows a plot of sensorresponse data over a temperature range of 17° C.-42° C. As shown in FIG.4 , the sensor response showed minimal variation over a substantialportion of the temperature range, which encompasses normal physiologicaltemperatures in humans. Even at temperatures when the beginnings ofresponse variability began to be observed (i.e., greater than 37° C.),the response variability was still below 2% over the 5° C. measurementintervals, as shown in the bar graph of FIG. 5 .

Example 2: Glucose Response. The coated sensor of Example 1 was testedat room temperature at variable glucose concentrations. As shown in FIG.6 , the sensor response as a function of glucose concentration wasapproximately linear at the fixed temperature.

Example 3: Biocompatibility Testing. Polyvinylpyridine copolymers withstyrene having an amine-free polyether arms with a structurecorresponding to Formula 12 (w=1) and defined by variables x, y and z,as specified in Table 1 below, were used for conducting severalbiocompatibility tests. Testing was conducted according to ISO 10993-1protocols and may be described in brief below.

Cytotoxicity. Polymers having amine-free polyether arms were tested forcytotoxicity under standard conditions using the Minimal EssentialElution Media Test. Results are shown in Table 1. Cytotoxicity testingwas conducted by applying an extract of the polymer (glucose-freeMinimal Essential Media) to a test cell monolayer, incubating, andscoring based upon the degree of monolayer destruction and the amount ofcell lysis. A score of ‘0’ represents no observable monolayerdestruction or cell lysis. Mild cytotoxicity is classified by a score of‘2’ or lower (<50% monolayer destruction with no extensive cell lysis).Scores of 2 or lower are considered acceptable criteria for certainpurposes under current U.S. Pharmacopeia and National Formularequirements (<USP 87>).

TABLE 1 Cytotoxicity Entry x y z (x + z):y Score 1 10 20 14 1.2 2 2 1216 16 1.75 0 3 14 12 18 2.67 0As shown in Table 1, increasing the ratio of polyethylene oxide topolypropylene oxide improved the cytotoxicity response.

Hemolysis. Hemolysis studies were conducted on the polymer of entry 3using an extract method (phosphate buffered saline) as specified in ASTMF 756. There was no difference in hemolysis between the extract and anegative control, meaning that the polymer of entry 3 was non-hemolyticwith a hemolysis index of 2 or below.

Mutagenicity. Mutagenicity studies were conducted on the polymer ofentry 3 using the Ames test. Extracts of the polymer did not meet therequirements for mutagenicity under this test.

Single Dose Systemic Irritation Studies. An extract of the polymer ofentry 3 was injected either intravenously or intraperitoneally. No signsof toxicity compared to the control were seen over the observationperiod.

Skin Irritation Studies. Skin irritation studies of an extract of thepolymer of entry 3 produced a sensitization response score of 0, meaningno visible erythema or edema.

Intracutaneous Irritation Studies. Intracutaneous irritation studies ofan extract of the polymer of entry 3 produced no abnormal clinical signscompared to the vehicle control over a 72-hour observation period.Calculated erythema and edema scores as compared to the control wereless than 1 (no to barely perceptible erythema or edema).

Implantation Studies. The polymer of entry 3 produced an irritant scoreof 0.2 when implanted, thereby classifying it as a non-irritant.

Unless otherwise indicated, all numbers expressing quantities and thelike in the present specification and associated claims are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the embodiments of the present invention. Atthe very least, and not as an attempt to limit the application of thedoctrine of equivalents to the scope of the claim, each numericalparameter should at least be construed in light of the number ofreported significant digits and by applying ordinary roundingtechniques.

One or more illustrative embodiments incorporating various features arepresented herein. Not all features of a physical implementation aredescribed or shown in this application for the sake of clarity. It isunderstood that in the development of a physical embodimentincorporating the embodiments of the present invention, numerousimplementation-specific decisions must be made to achieve thedeveloper's goals, such as compliance with system-related,business-related, government-related and other constraints, which varyby implementation and from time to time. While a developer's effortsmight be time-consuming, such efforts would be, nevertheless, a routineundertaking for those of ordinary skill in the art and having benefit ofthis disclosure.

While various systems, tools and methods are described herein in termsof “comprising” various components or steps, the systems, tools andmethods can also “consist essentially of” or “consist of” the variouscomponents and steps.

As used herein, the phrase “at least one of” preceding a series ofitems, with the terms “and” or “or” to separate any of the items,modifies the list as a whole, rather than each member of the list (i.e.,each item). The phrase “at least one of” allows a meaning that includesat least one of any one of the items, and/or at least one of anycombination of the items, and/or at least one of each of the items. Byway of example, the phrases “at least one of A, B, and C” or “at leastone of A, B, or C” each refer to only A, only B, or only C; anycombination of A, B, and C; and/or at least one of each of A, B, and C.

Therefore, the disclosed systems, tools and methods are well adapted toattain the ends and advantages mentioned as well as those that areinherent therein. The particular embodiments disclosed above areillustrative only, as the teachings of the present disclosure may bemodified and practiced in different but equivalent manners apparent tothose skilled in the art having the benefit of the teachings herein.Furthermore, no limitations are intended to the details of constructionor design herein shown, other than as described in the claims below. Itis therefore evident that the particular illustrative embodimentsdisclosed above may be altered, combined, or modified and all suchvariations are considered within the scope of the present disclosure.The systems, tools and methods illustratively disclosed herein maysuitably be practiced in the absence of any element that is notspecifically disclosed herein and/or any optional element disclosedherein. While systems, tools and methods are described in terms of“comprising,” “containing,” or “including” various components or steps,the systems, tools and methods can also “consist essentially of” or“consist of” the various components and steps. All numbers and rangesdisclosed above may vary by some amount. Whenever a numerical range witha lower limit and an upper limit is disclosed, any number and anyincluded range falling within the range is specifically disclosed. Inparticular, every range of values (of the form, “from about a to aboutb,” or, equivalently, “from approximately a to b,” or, equivalently,“from approximately a-b”) disclosed herein is to be understood to setforth every number and range encompassed within the broader range ofvalues. Also, the terms in the claims have their plain, ordinary meaningunless otherwise explicitly and clearly defined by the patentee.Moreover, the indefinite articles “a” or “an,” as used in the claims,are defined herein to mean one or more than one of the elements that itintroduces. If there is any conflict in the usages of a word or term inthis specification and one or more patent or other documents that may beincorporated herein by reference, the definitions that are consistentwith this specification should be adopted.

What is claimed is the following:
 1. A polymeric membrane compositioncomprising: a polymer backbone comprising one or more side chains thatcomprise a heterocycle; and an amine-free polyether arm appended, via analkyl spacer or a hydroxy-functionalized alkyl spacer, to theheterocycle of at least a portion of the one or more side chains;wherein the amine-free polyether arm comprises at least one polyethyleneoxide block and at least one polypropylene oxide block, the amine-freepolyether arm being bound to a heterocyclic or heteroaromatic nitrogenatom in a side chain of the polymer backbone.
 2. The polymeric membranecomposition of claim 1, wherein the polymer backbone comprises apolyvinylpyridine or a polyvinylimidazole.
 3. The polymeric membranecomposition of claim 2, wherein the polymer backbone comprises acopolymer of vinylpyridine and styrene.
 4. The polymeric membranecomposition of claim 1, wherein the amine-free polyether arm has astructure of

wherein w is 0 or 1, x ranges between about 4 and about 24, y rangesbetween about 8 and about 60, and z ranges between about 6 and about 36.5. The polymeric membrane composition of claim 4, wherein x rangesbetween about 8 and about 16, y ranges between about 10 and about 32,and z ranges between about 10 and about
 20. 6. The polymeric membranecomposition of claim 4, wherein x≤z.
 7. The polymeric membranecomposition of claim 4, wherein a ratio of (x+z):y is at least about1.7:1.
 8. The polymeric membrane composition of claim 4, wherein a ratioof (x+z):y ranges between about 1.7:1 and about 5:1.
 9. The polymericmembrane composition of claim 1, further comprising: asulfonate-containing arm appended to at least a portion of the one ormore side chains.
 10. The polymeric membrane composition of claim 1,further comprising: an amine-free polyethylene oxide arm appended, viaan alkyl spacer or a hydroxy-functionalized alkyl spacer, to theheterocycle of at least a portion of the one or more side chains. 11.The polymeric membrane composition of claim 1, further comprising: acrosslinker appended to at least a portion of the one or more sidechains and adjoining a first polymer backbone to a second polymerbackbone.
 12. The polymeric membrane composition of claim 1, wherein thepolymeric membrane composition meets or exceeds ISO 10993-1 standards.13. An analyte sensor comprising: a sensing region; and a polymericmembrane composition overlaying the sensing region; wherein thepolymeric membrane composition comprises a polymer backbone comprisingone or more side chains that comprise a heterocycle, and an amine-freepolyether arm appended, via an alkyl spacer or a hydroxy-functionalizedalkyl spacer, to the heterocycle of at least a portion of the one ormore side chains; and wherein the amine-free polyether arm comprises atleast one polyethylene oxide block and at least one polypropylene oxideblock, the amine-free polyether arm being bound to a heterocyclic orheteroaromatic nitrogen atom in a side chain of the polymer backbone.14. The analyte sensor of claim 13, wherein the sensing region comprisesan enzyme.
 15. The analyte sensor of claim 13, wherein the polymerbackbone comprises a polyvinylpyridine or a polyvinylimidazole.
 16. Theanalyte sensor of claim 15, wherein the polymer backbone comprises acopolymer of vinylpyridine and styrene.
 17. The analyte sensor of claim13, wherein the amine-free polyether arm has a structure of

wherein w is 0 or 1, x ranges between about 4 and about 24, y rangesbetween about 8 and about 60, and z ranges between about 6 and about 36.18. The analyte sensor of claim 17, wherein x ranges between about 8 andabout 16, y ranges between about 10 and about 32, and z ranges betweenabout 10 and about
 20. 19. The analyte sensor of claim 17, wherein x≤z.20. The analyte sensor of claim 17, wherein a ratio of (x+z):y is atleast about 1.7:1.
 21. The analyte sensor of claim 17, wherein a ratioof (x+z):y ranges between about 1.7:1 and about 5:1.
 22. The analytesensor of claim 13, further comprising: a sulfonate-containing armappended to at least a portion of the one or more side chains.
 23. Theanalyte sensor of claim 13, further comprising: an amine-freepolyethylene oxide arm appended, via an alkyl spacer or ahydroxy-functionalized alkyl spacer, to the heterocycle of at least aportion of the one or more side chains.
 24. The analyte sensor of claim13, further comprising: a crosslinker appended to at least a portion ofthe one or more side chains and adjoining a first polymer backbone to asecond polymer backbone.
 25. The polymeric membrane composition of claim1, wherein the polymeric membrane composition is temperature-insensitiveto at least glucose permeability over a temperature range of about 15°C. to about 45° C.
 26. The polymeric membrane composition of claim 25,wherein the polymeric membrane composition meets or exceeds ISO 10993-1standards.